Interleukin-6 (IL-6) is a cytokine known as stimulating B cell factor or known as interferon-β2, which is a non-glycosylated polypeptide chain comprised of 185 amino acids. IL-6 was discovered as a differentiation factor involved in the activation of B lymphocytic cells (Hirano, T.; Yasukawa, K.; Harada, H.; Taga, T.; Watanabe, Y.; Matsuda, T.; Kashiwamura, S.; Nakajima, K.; Koyama, K.; Iwamatsu, A.; et al., Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 1986, 324 (6092), 73-6), and then identified as a multifunctional cytokine which affects differentiation and proliferation of T cells, differentiation of nerve cells, formation of osteoclast, production of acute phase protein in hepatocyte, etc. (Akira, S.; Taga, T.; Kishimoto, T., Interleukin-6 in biology and medicine. Adv Immunol 1993, 54, 1-78). In addition, IL-6 is secreted from various cells including T cell and macrophage, and plays a role in maintaining the homeostasis of living bodies by inducing on immune reaction and inhibiting TNF-α, IL-1, etc., and further regulates the expression of a specific gene in the liver when an acute phase immune reaction occurs and controls the survival of normal plasmablastic cells (Ishihara, K.; Hirano, T., IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev 2002, 13 (4-5), 357-68).
Meanwhile, it has been reported that IL-6 reduces insulin sensitivity, and thus is also involved in the induction of insulin-resistant diabetes; induces blood coagulation by promoting secretion of cellular adhesion factors and secretion of fibrinogen in hepatic tissues; increases cholesterol synthesis or decreases secretion of cholesterol; and induces arteriosclerosis through upregulation of Lecithin cholesterol acyltransferase (LCAT) and apolipoprotein A-1 (apo A-1) genes (Omoigui, S., Cholesterol synthesis is the trigger and isoprenoid dependent interleukin-6 mediated inflammation is the common causative factor and therapeutic target for atherosclerotic vascular disease and age-related disorders including osteoporosis and type 2 diabetes. Med Hypotheses 2005, 65 (3), 559-69; Yudkin, J. S.; Kumari, M.; Humphries, S. E.; Mohamed-Ali, V., Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis 2000, 148 (2), 209-14). Further, it has also been reported as the result of research that in cases where the concentration of IL-6 involved in inflammation formation increases, the risk of an onset of heart diseases and the fatality rate thereof are increased. Diseases caused by the increase of the production of IL-6 include Alzheimer disease, rheumatoid arthritis, inflammation, myocardial infarction, Paget's disease, osteoporosis, solid tumors (RCC), bladder cancer, prostate cancer, Castleman syndrome, etc. (Ishihara, K.; Hirano, T., IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev 2002, 13 (4-5), 357-68; Lindmark, E.; Diderholm, E.; Wallentin, L.; Siegbahn, A., Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: effects of an early invasive or noninvasive strategy. JAMA 2001, 286 (17), 2107-13).
Recently, the number of patients suffering from inflammation-related diseases induced by abnormal IL-6 activity, including rheumatoid arthritis, Castleman syndrome, Crohn's disease, osteoporosis, cancer cachexia, arteriosclerosis, diabetes, etc. is rapidly tending upwards. Although research to develop an agent for treatment of metabolic diseases represented by rheumatoid arthritis, osteoporosis, arteriosclerosis and diabetes has been made worldwide, the development of an agent for treatment thereof has been unsatisfactory so far. IL-6 has recently came under interest as an important factor for inflammatory reaction deeply related to the onset and progress of such metabolic diseases.
Meanwhile, interleukin 6 receptor (IL-6R) has been known as a type I cytokine receptor called Cluster of Differentiation 126 (CD126), and transmits its biological activities through the medium of 2 kinds of cellular proteins. Respective proteins are comprised of polypeptide chains of α-subunit and β-subunit. α-Subunit is a ligand binding chain having the molecular weight of about 80 kDa, and is designated as gp80 or CD126. It is present in the form of soluble IL-6 R mainly comprised of its extracellular domain, as well as in the form of a membrane-binding form, which penetrates the cell membrane and is expressed in the cell membrane. β-Subunit is gp130 or CD130, and has been known as having the molecular weight of 130 kDa. It is a membrane-binding protein and takes part in signal transduction (Taga, T.; Kawanishi, Y.; Hardy, R. R.; Hirano, T.; Kishimoto, T., Receptors for B cell stimulatory factor 2. Quantitation, specificity, distribution, and regulation of their expression. J Exp Med 1987, 166 (4), 967-81).
In addition, it is a domain commonly contained in cytokine family such as oncostatin M (OSM), leukemia inhibitory factor (LIF), IL-11, cardiotrophin-1 (CT-1), and ciliary neurotrophic factor (CNTF), and is found in most living organs including the heart, kidney, spleen, liver, lung, placenta, brain, etc. (Kang, B. S.; Chung, E. Y.; Yun, Y. P.; Lee, M. K.; Lee, Y. R.; Lee, K. S.; Min, K. R.; Kim, Y., Inhibitory effects of anti-inflammatory drugs on interleukin-6 bioactivity. Biol Pharm Bull 2001, 24 (6), 701-3; Jones, S. A.; Horiuchi, S.; Topley, N.; Yamamoto, N.; Fuller, G. M., The soluble interleukin 6 receptor: mechanisms of production and implications in disease. FASEB J 2001, 15 (1), 43-58). Further, IL-6 and IL-6R form the IL-6/IL-6R complex, which is then bound to gp130, thereby transmitting the biological activities of IL-6 into cells.
In 1994, a signal transduction system utilizing Jak family, tyrosine kinase, and STAT family, a transcription factor, as the main mediators for signal transduction was discovered. Various cytokines including IL-6, and IFNs and growth factors have signal transduction system mechanism in common. Upon initiation of the stimulation Jak1, Jak2, and Tyk2 as gp130-associated kinase are activated, and the cytoplasmic tail of gp130 is phosphorylated. Phosphotyrosine residues of gp-130 is a docking site, which is mainly paired with SH2 domains of STAT3 and STAT1. Then, STAT is phosphorylated and forms a dimer, which is then migrated into a nucleus to regulate the transcription of the target gene (Heinrich, P. C.; Behrmann, I.; Muller-Newen, G.; Schaper, F.; Graeve, L., Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 1998, 334 (Pt 2), 297-314).
Ras-Raf pathway allows the binding of tyrosine phosphatase SHP2 to phosphorylated gp130, and allows the connection with mitogen-activated protein kinase (MAPK) pathway. Finally, NF-IL-6 (a C/EBP family member) and AP-1 (c-Jun, c-Fos) as the transcription factor are activated to cause the biological reaction. It has been expected that a series of MAPK pathway related to Ras signal transduction IL-6 plays an important role in cell differentiation and proliferation.
Research to reveal the role of IL-6 in a series of signal transduction systems induced by IL-6 more in more detail is in progress, and thus the exact information on respective steps is being revealed. According to this, the complexity of inflammatory reaction is being amplified, and more minor new target procedures for the respective diseases are being derived therefrom. Therefore, if IL-6 inhibitors are developed as the target of the signal transduction system induced by IL-6, it helps to identify the mechanism of the signal transduction system, and at the same time, enables the development of medical products.
In the study of IL-6 activity inhibitors related thereto, antibody against IL-6 (anti-IL-6 antibody), antibody against IL-6R (anti-IL-6 receptor antibody) and antibody against gp130 (anti-gp130 antibody), IL-6 modification, IL-6 or IL-6R partial peptides, etc. have been reported (Heinrich, P. C.; Behrmann, I.; Haan, S.; Hermanns, H. M.; Muller-Newen, G.; Schaper, F., Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 2003, 374 (Pt 1), 1-20; Novick, D.; Engelmann, H.; Revel, M.; Leitner, O.; Rubinstein, M., Monoclonal antibodies to the soluble human IL-6 receptor: affinity purification, ELISA, and inhibition of ligand binding. Hybridoma 1991, 10 (1), 137-46; Huang, Y. W.; Vitetta, E. S., A monoclonal anti-human IL-6 receptor antibody inhibits the proliferation of human myeloma cells. Hybridoma 1993, 12 (5), 621-30; Mihara, M, Preventives or remedies for sensitized T cell-related diseases containing IL-6 antagonists as the active ingredient. WO9842377, 1998).
Particularly, it has been reported that tocilizumab as a IL-6R neutralizing antibody (MRA) alleviates the symptoms of patients suffering from Castleman syndrome, Crohn's disease and rheumatoid arthritis [Nishimoto, N., Clinical studies in patients with Castleman's disease, Crohn's disease, and rheumatoid arthritis in Japan. Clin Rev Allergy Immunol 2005, 28 (3), 221-30).
Madindoline A developed as an IL-6 activity inhibitor by the Kitasato Institute of Japan is a non-cytotoxic indole alkaloid separated from the fermentation culture solution of Streptomyces nitrosporeus K930711, and forms a non-covalent bond competitively with the extracellular domain of gp130 (Structural Formula 1). This compound inhibits the formation of osteoclasts induced by IL-6 through the inhibition of the homodimerization of gp130 to inhibit JAK/STAT signal transduction procedures, and has an effect of alleviating the symptoms of osteoporosis in menopause-induced mice. However, madindoline A has the disadvantages that it is difficult to synthesize in a mass scale due to complex synthetic procedures, and the production from microorganisms is also of an extremely minor yield (Hayashi, M.; Rho, M. C.; Enomoto, A.; Fukami, A.; Kim, Y. P.; Kikuchi, Y.; Sunazuka, T.; Hirose, T.; Komiyama, K.; Omura, S., Suppression of bone resorption by madindoline A, a novel nonpeptide antagonist to gp130. Proc Natl Acad Sci USA 2002, 99 (23), 14728-33).
As other IL-6R inhibitor, A20S,21-epoxy-resibufogenin-3-formate (ERBF) is a material discovered through screening of natural substances, and was separated from bufadienolide.

It inhibits cancer cachexia induced by Colon-26. However, since the total synthetic method for the preparation of ERBF has not yet been developed, ERBF also has the disadvantage that its production through separation from natural substances is extremely limited (Enomoto, A.; Rho, M. C.; Fukami, A.; Hiraku, O.; Komiyama, K.; Hayashi, M., Suppression of cancer cachexia by 20S,21-epoxy-resibufogenin-3-acetate-a novel nonpeptide IL-6 receptor antagonist. Biochem Biophys Res Commun 2004, 323 (3), 1096-102).
As described above, although basic research of various diseases, which can be induced by abnormal IL-6 activity has been ongoing, much of their attack mechanisms have not yet been clearly defined, and thus the study of various vital phenomena caused by the inhibition of IL-6 activity is incomplete.
That seems to be caused by the poor progress of the development of low molecular materials, which specifically inhibit the activity of IL-6. Therefore, if low molecular compounds, which can be synthesized on a large scale and specifically inhibit the activity of IL-6, could be developed, it is considered that the relationship between IL-6 and related diseases will be more exactly defined, and the compounds thus developed can be utilized for the development of medical products. Thus, the present inventor has identified that novel benzoxazole derivatives can satisfy such requirements, thereby completing the present invention.